The Section on Molecular Neuroscience studies the molecular mechanisms responsible for the development of chemical coding in the central nervous system (CNS), from signals initiated at the cell membrane by neurotrophic factors and neurotransmitters, to the cis-acting elements on neuropeptide and neurotransmitter-associated genes responsible for establishment of chemically coded ionotropic and metabotropic neurotransmission. The ultimate goal of the chemical coding project is molecular understanding of the factors governing late nervous system phenotypic development, and the use of neurotransmitter-specific synthetic operons to understand and restore neurotransmitter balance in animal models of human CNS disease.We have made progress this year in three related areas within the project. First, we have demonstrated that the cholinergic gene locus (CGL), encoding the vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) is regulated independently in motor and non-motor cholinergic neurons. This work sets the stage for specific targeting of trans-genes to separate divisions of the cholinergic nervous system for the study of higher functions mediated cholinergically, such as sleep, arousal and cognition. Second, we have identified in neuroblastoma cells a new mode of regulating cell-specific expression of neuropeptide genes involving differential cellular expression of specialized members of the AP-1 transcriptional regulator family. Third, we have demonstrated that neuropeptide gene regulation involves signaling molecules, including calcineurin, previously thought to exert their actions on gene transcription mainly in the immune system. Progress in areas two and three will enable the exploration of chemical coding of neurotransmission in vivo regulated indirectly by cell-specific expression of signal transduction pathway components, in addition to factors that act directly on neuron-specific genes. These findings should provide new targets for pharmacological manipulatiion of neuronal gene expression, and may provide insight into the mechanisms of cellular - VAChT cholinergic gene locus VMAT VIP PACAP signal transduction neurotransmission calcineurin